Pancreatic stellate cells in pancreatic cancer: In focus

Allam, Amr H.; Thomsen, Andreas; Gothwal, Monika; Saha, Dibyajyoti; Maurer, Jochen; Brunner, Thomas

doi:10.1016/j.pan.2017.05.390

Cited by 39 publications

(35 citation statements)

References 71 publications

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“…PSCs are located in the periacinar spaces in a quiescent state in normal healthy pancreas, but can be activated by many extracellular stimuli including pro-inammatory cytokines, oxidative stress, hypoxia and increased interstitial pressure. 1,2 The activated PSCs can express a-smooth muscle actin (a-SMA) and synthesize a large amount of extracellular matrix (ECM) proteins leading to excessive brosis of the pancreas. For example, in human pancreatic cancer, the brotic stroma can account for up to 90% of the tumor volume, and the brotic microenvironment has been proven to support tumorigenesis, chemoresistance, invasion and progression of tumors.…”

Section: Introductionmentioning

confidence: 99%

Retracted Article: ASIC1a involves acidic microenvironment-induced activation and autophagy of pancreatic stellate cells

Wang

Pan

et al. 2018

RSC Adv.

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Section: Introductionmentioning

confidence: 99%

Retracted Article: ASIC1a involves acidic microenvironment-induced activation and autophagy of pancreatic stellate cells

Wang

Pan

et al. 2018

RSC Adv.

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“…Under homeostatic conditions, quiescent pancreatic stellate cells (qPSCs) localize in basolateral aspects of acinar cells, or surround perivascular and periductal regions. qPSCs are capable of expressing several protein markers, such as glial fibrillary acidic protein (GFAP), synemin, and desmin, most of which are not specific [ 15 , 16 ]. Even though the physiological roles of qPSCs haven’t been fully delineated, some functions are postulated and widely recognized.…”

Section: Introductionmentioning

confidence: 99%

The critical roles of activated stellate cells-mediated paracrine signaling, metabolism and onco-immunology in pancreatic ductal adenocarcinoma

et al. 2018

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant diseases worldwide. It is refractory to conventional treatments, and consequently has a documented 5-year survival rate as low as 7%. Increasing evidence indicates that activated pancreatic stellate cells (PSCs), one of the stromal components in tumor microenvironment (TME), play a crucial part in the desmoplasia, carcinogenesis, aggressiveness, metastasis associated with PDAC. Despite the current understanding of PSCs as a “partner in crime” to PDAC, detailed regulatory roles of PSCs and related microenvironment remain obscure. In addition to multiple paracrine signaling pathways, recent research has confirmed that PSCs-mediated tumor microenvironment may influence behaviors of PDAC via diverse mechanisms, such as rewiring metabolic networks, suppressing immune responses. These new activities are closely linked with treatment and prognosis of PDAC. In this review, we discuss the recent advances regarding new functions of activated PSCs, including PSCs-cancer cells interaction, mechanisms involved in immunosuppressive regulation, and metabolic reprogramming. It’s clear that these updated experimental or clinical studies of PSCs may provide a promising approach for PDAC treatment in the near future.

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“…The tumour microenvironment is a complex system of dynamic interdependencies. Fibroblasts and related cells are integral to PDAC's aggression and resistance, and are keys to building successful therapeutic combinations 7,9,12,13,[22][23][24]30,31,64 . Our experiments reveal that active metastatic fibroblasts may aid the formation and colonization of pancreatic cancer by promoting angiogenesis at the boundary of cancer cells and resisting anti-angiogenic compounds like sunitinib.…”

Section: Discussionmentioning

confidence: 99%

Metastasis-associated fibroblasts promote angiogenesis in metastasized pancreatic cancer via the CXCL8 and the CCL2 axes

Pausch

Aue

Wirsik

et al. 2020

Sci Rep

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The characteristic desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a key contributor to its lethality. This stromal microenvironment is populated by cancer-associated fibroblasts (CAFs) that interact with cancer cells to drive progression and chemo-resistance. Research has focused on CAFs in the primary tumour but not in metastases, calling into question the role of analogous metastasis-associated fibroblasts (MAFs). We infer a role of MAFs in murine hepatic metastases following untargeted treatment with the anti-angiogenic drug sunitinib in vivo. Treated metastases were smaller and had fewer stromal cells, but were able to maintain angiogenesis and metastasis formation in the liver. Furthermore, sunitinib was ineffective at reducing MAFs alongside other stromal cells. We speculate that cancer cells interact with MAFs to maintain angiogenesis and tumour progression. Thus, we tested interactions between metastatic pancreatic cancer cells and fibroblasts using in vitro co-culture systems. Co-cultures enhanced fibroblast proliferation and induced angiogenesis. We identify carcinoma-educated fibroblasts as the source of angiogenesis via secretions of CXCL8 (aka IL-8) and CCL2 (aka MCP-1). Overall, we demonstrate that metastasis-associated fibroblasts have potential as a therapeutic target and highlight the CXCL8 and CCL2 axes for further investigation. Ductal adenocarcinoma of the pancreas (PDAC) is an aggressive cancer with slim chances of survival 1-3. Once metastasized, chemotherapy provides the main treatment option but standard regimes offer minimal survival extension 4-6. PDAC's chemo-resistance may involve the characteristic desmoplastic stroma that comprises most of the tumour tissue 7-11. The stroma contains a population of carcinoma-associated fibroblasts (CAFs) that can differentiate from pancreatic stellate cells, among other sources 12,13. CAFs surround cancer cells and provide structural and signalling functions 9,13-21. Thus, the mechanisms that activate stromal fibroblasts during cancer progression have potential as therapeutic targets 12,13,22-24. CAFs are a target for novel PDAC therapies, but there is controversy over their role in tumour progression 13. On one hand, stromal depletion from PDAC-like tumours using Hedgehog (Hh) pathway inhibitors can stimulate angiogenesis and enhance drug delivery 25. On the other, stromal myofibroblast depletion can suppress angiogenesis and enhance tumour progression 26-28. Together, these studies imply that the stroma can have both a protective role for the tumour 28 but also restrict its progression 27,29. Importantly, the balance between these roles may depend on sub-populations of different fibroblast types in the microenvironment 22,30. Clearly, improved treatment requires a better understanding of the stroma and its fibroblastic populations. However, even less is known about cancer-fibroblast interactions during metastasis, despite the largely stromatic composition of metastatic tissue 7-11,22,23,31,32. Metastasis-associated fibroblasts (M...

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Pancreatic stellate cells in pancreatic cancer: In focus

Cited by 39 publications

References 71 publications

Retracted Article: ASIC1a involves acidic microenvironment-induced activation and autophagy of pancreatic stellate cells

Retracted Article: ASIC1a involves acidic microenvironment-induced activation and autophagy of pancreatic stellate cells

The critical roles of activated stellate cells-mediated paracrine signaling, metabolism and onco-immunology in pancreatic ductal adenocarcinoma

Metastasis-associated fibroblasts promote angiogenesis in metastasized pancreatic cancer via the CXCL8 and the CCL2 axes

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